Morphine effect on the body. What is morphine. Use with extreme caution

What is morphine and where is it used? In its raw form, the drug "Morphine" looks like a white crystalline powder. "Morphine" is an obsolete name for the drug. The name of this substance refers to the Greek god Morpheus, who, according to legend, controlled dreams. It is a drug that is an opium alkaloid. It is made from the processed juice of the opium poppy. In addition, small amounts of morphine can be found in herbs like stephania, sinomenium, moonseed, etc. Let's look at what morphine is below.

Historical reference

Morphine is a drug that has a sedative, analgesic, sedative and hypnotic effect. Drugs developed on the basis of morphine have been used in medical practice since 1805. All hospitals during the American Civil War were supplied with this drug. It was administered to wounded soldiers as an anesthetic intramuscularly or intravenously after surgery, which greatly alleviated the plight of the patients. That's what morphine is. The content of this concept interests many.

Main disadvantage

The main disadvantage of the drug was its narcotic nature. This caused rapid addiction during use. Quite soon, the condition into which prolonged use of the drug led the patient began to be called a soldier’s disease. A well-known fact is that at the beginning of the 20th century the drug was used not only for military purposes, but also by doctors who thus wanted to stop the feeling of fatigue. Not everyone knows what morphine is and what the properties of the substance are.

Form and properties

The drug is available in several forms. Morphine can be in tablets and solutions for intramuscular or intravenous administration. As for the properties of the drug, several characteristic features stand out:

1. Morphine is produced in the form of needle-shaped crystals or white powder. It tends to turn yellow or gray during long-term storage.

2. The drug is diluted slowly in water, and it is almost impossible to dissolve it in an alcohol solution.

3. Incompatible with alkalis.

4. The morphine solution requires half an hour of sterilization at a temperature of 100 degrees Celsius.

5. To stabilize the solution, hydrochloric acid is added to it.

6. The powder melts at 254 degrees Celsius.

7. The specific rotation value of the solution is 2%.

8. Ignition occurs at 261 degrees.

9. The powder spontaneously ignites at 349 degrees Celsius.

Let's look at the instructions for morphine briefly.

Pharmacodynamics

Morphine belongs to the category of narcotic drugs. Included in the group of opioid analgesics. The drug can cause euphoria, create a feeling of peace of mind, reduce pain, improve mood and show bright prospects, even if the real state of affairs leaves much to be desired.

Addictive

Such properties of morphine provoke the development of mental and even physical dependence on the drug. If the dosage is exceeded, it becomes a powerful hypnotic. In addition, the substance can slow down the speed of conditioned reflexes, reduce the excitability of the cough center and cause miosis. The drug also increases muscle tone of internal organs, which can cause spasm of the sphincter of Oddi, as well as the biliary tract. Another property of the drug is the weakening of intestinal motility. In this case, emptying accelerates and gastric peristalsis increases.

What is morphine and why is it needed?

As an anesthetic, it is prescribed subcutaneously, intravenously or intramuscularly. However, other options for use are also possible, for example, orally, rectally, epidurally or intrathecally, that is, under the membrane of the spinal cord.

The drug is absorbed very quickly. Up to 40% of the active substance binds to plasma proteins. Morphine can cross the placenta and depress the respiratory function of the fetus. The same goes for breast milk. That is, it should absolutely not be used during pregnancy and lactation. When administered intramuscularly, the peak effectiveness of the drug is achieved after 15 minutes. Distribution through the bloodstream occurs after 35 minutes, and the effect lasts up to 5 hours.

Indications for use

Morphine is prescribed as a pain reliever for injuries and diseases accompanied by significant pain. It is also used during preparatory procedures before and after surgery. Sometimes the drug can be prescribed for severe cough and shortness of breath, insomnia and other symptoms accompanying acute heart failure.

During the X-ray

In some cases, it is permissible to use morphine during an X-ray examination of the gallbladder, stomach or duodenum. The drug helps to increase the muscle tone of the stomach, enhances peristalsis and accelerates the emptying process. All this makes it easier for specialists to diagnose cancer of internal organs or ulcers.

Oncology and other applications

The main area of ​​application of morphine is oncology. The drug is able to quickly relieve pain and alleviate the patient’s condition. Thus, this drug has the following properties:

1. Suppression of painful sensations in cancer, trauma, unstable angina and myocardial infarction.

2. Used in the field of anesthesiology during surgery as an additional tool.

3. If other drugs are ineffective, morphine is used during childbirth, for cough or pulmonary edema.

4. Discharged before an x-ray of the gallbladder, stomach or duodenum. We have explained what morphine is.

Contraindications

Contraindications to taking morphine are:

1. Hypersensitivity to the components of the drug.

2. Depression of respiratory function, for example, as a result of alcohol or drug intoxication.

3. Depressed state of the central nervous system.

4. Paralytic intestinal obstruction.

5. Conducting epidural or spinal anesthesia.

Carefully

These are absolute contraindications. There are also situations where morphine should be used with extreme caution. It can be:

1. Pain in the abdominal area of ​​unknown origin.

2. Emotional lability.

3. An attack of bronchial asthma.

4. Arrhythmia.

5. Cramps.

6. Presence of drug addiction.

7. Alcoholism.

8. Suicidal tendencies.

9. Gallstone disease.

10. Carrying out surgical intervention in the gastrointestinal tract and urinary system.

Also, the use of the drug requires caution in case of brain injuries, liver or kidney failure, prostatic hyperplasia, hypothyroidism, stricture of the urethra, severe inflammatory bowel diseases, epileptic syndrome, as well as after surgery in the biliary tract.

This is what morphine is in medicine.

Dosage

Morphine and its derivatives are included in lists I and II of narcotic drugs. For this reason, some drugs have strictly limited access, and some of them are prohibited for sale in Russia. However, morphine-based drugs are still used in hospitals. It can be used only as prescribed by a doctor and in the dosage specified by a specialist. The latter depends on the severity of the patient’s condition and the sensitivity of his body to the drug.

What is morphine and what is it for, patients often ask.

A single dosage for an adult patient is 10-20 mg; if we are talking about capsules, then one dose is up to 100 mg. For intramuscular and intravenous administration, the dosage is 10 mg, but it should not exceed 50 mg per day.

Side effects

If the dosage prescribed by the doctor is exceeded, the patient may experience a number of side effects, such as:

1. Confusion.

2. Cold and sticky profuse sweat.

3. Fatigue.

4. Drowsiness.

6. Bradycardia.

7. Intracranial hypertension.

8. Nervousness.

9. Hypothermia.

10. Slow and difficult breathing.

11. Anxiety.

12. Dry mouth.

13. Delirious psychosis.

14. Lower blood pressure.

15. Dizziness.

16. Convulsions.

17. Hallucinations.

18. Muscle rigidity.

It is important not only to know what morphine is, but also to understand the following. Dependence on it can become a serious illness that requires immediate intervention from appropriate specialists. This is due to the fact that addiction can cause severe overdose, which may well result in death.

Morphine or, in other words, Morphine in its pure form is presented in the form of a white powder. In addition to its sedative and hypnotic effects on the body, morphine is used for pain relief in cancer patients. How to use the medicine correctly and what are the features of its use?

General characteristics of cancer pain and features of drug use for cancer

Malignant tumors are one of the most dangerous pathologies in modern medicine. Dangerous consequences are expressed not only in possible death, but also in the occurrence of severe intractable pain, which brings a lot of suffering to a person. Every person suffering from a malignant neoplasm of any location experiences pain at every stage of its development.

Often, severe pain occurs with stage 4 cancer, when metastases are observed, radiating from the primary focus to other organs and systems. At this time, the doctor takes all measures to ease the intensity of pain and the general well-being of the patient. According to research, almost half of all cancer patients do not have complete control over their symptoms, and a quarter of them die not from the most malignant lesion of the body, but from unbearable pain.

Before understanding how Morphine works in anesthetizing a malignant tumor, it is worth considering what the mechanism of pain in this case is and how it arises. So, to determine the necessary method of symptom management for cancer, first of all, find out the type of pain:

1. Nociceptive. Pain impulses from nociceptors to the brain are transmitted using peripheral nerves. Nociceptive pain, in turn, is divided into somatic (sharp or dull), visceral (not clearly defined) and associated with previous invasive surgery.
2. Neuropathic. The pain syndrome in this case is caused by damage to the nervous system. If a person is diagnosed with advanced cancer of any location, neuropathic pain can be caused by infiltration of the nerve root, exposure to a chemotherapy drug or radiation from radiation therapy.

Over time, the progression of cancer, the pain syndrome only increases in intensity, reaching maximum levels when the disease reaches stage 4. The most effective is the use of Morphine for cancer, which began to be used for such purposes back in 1950. Later, the World Health Organization decided to take this medicine every 4 hours to achieve the desired pain relief.

In those years, Morphine was used only in tablet form for the development of cancer. Today there are also injections (injections) of the drug. The elimination of different forms of Morphine from the body occurs over different periods of time. The injection form of the drug has immediate release and rapid absorption. For this reason, morphine injections can be taken several times a day. If we talk about the tablet form of the drug, its elimination from the body is quite slow, which makes it possible to use Morphine only once a day.

Internal use of Morphine helps relieve moderate to severe pain. If used correctly, the medicine is quite safe and effective. Otherwise, especially if the drug is abused, it can cause addiction and depression of respiratory function.

1. Individual determination of the dosage of the drug, taking into account the intensity and nature of the pain.
2. The exact time of taking Morphine during the development of cancer, which is determined by the attending physician based on the individual characteristics of the development of the pathology.
3. “Ascending” use of the drug, namely, from the maximum dosage of weak opiates to the minimum dosage of Morphine.
4. Tablets are considered the most gentle and effective forms of medicine, but when used correctly, in order to avoid addiction.

To eliminate pain caused by the development of a malignant tumor, tablets are taken at a rate of 0.2-0.8 mg/kg, every 12 hours. Granules of the drug, which are intended for the preparation of a suspension and internal use, are prepared as follows: 20, 30 or 60 mg of granules are diluted in 10 ml of water, 100 mg in 20 ml, 200 mg in 30 ml. The suspension must be mixed well and drunk immediately after preparation. The dose for one injection of Morphine is 1 mg. In this case, the drug is administered subcutaneously. You can inject the medicine into a vein or muscle, but in a different dosage - 10 mg.

Under what circumstances is it prohibited to use the medicine?

In addition to such a high effectiveness of Morphine used for malignant neoplasms, there are also contraindications, which can be absolute and relative. The first type includes:

• the occurrence of pathologies in the body that cause depression of the central nervous system or respiration;
• development of intestinal obstruction;
• systematic seizures;
• frequent increase in intracranial pressure;
• past trauma to the skull;
• psychosis due to alcohol dependence or other acute alcohol pathology;
• development of bronchial asthma, cardiac arrhythmia, heart failure caused by chronic pulmonary disease;
• severe general condition, which is observed after surgical intervention on the biliary tract;
• development of pathologies of abdominal organs requiring surgical intervention;
• concomitant use of monoamine oxidase inhibitors (prohibition on the use of Morphine for two weeks after the end of their use);
• individual intolerance to Morphine components.

Relative contraindications to taking the drug for cancer are:

• the course of chronic obstructive pulmonary disease;
• suicidal tendencies in the patient;
• alcohol addiction;
• development of gallstone disease;
• epilepsy;
• operations that were previously performed on the gastrointestinal tract or urinary tract;
• development of renal or liver failure;
• development of hypothyroidism;
• in men – the occurrence of prostate hyperplasia;
• the course of severe inflammatory bowel pathology.

Elderly people and children should also take Morphine carefully. In such cases, the medicine is prescribed only by a specialist and taking into account the peculiarities of the course of oncological pathology. During pregnancy and lactation, the drug is used in case of emergency.

Adverse symptoms and overdose

Side symptoms can occur from many organs and systems in the body. If you take Morphine incorrectly, without consulting your doctor or in violation of his recommendations, you can cause the following negative manifestations:

• from the central nervous system and sensory organs: headaches, dizziness, a feeling of constant anxiety, apathy towards other people, nightmares at night, paresthesia, increased intracranial pressure, muscle twitching, inability to coordinate movement, convulsive syndrome, disturbance of the visual system (turbidity before the eyes), disturbance of taste, the appearance of ringing in the ears;
• from the cardiovascular system: development of bradycardia, tachycardia, heart rhythm disturbances, low or high blood pressure, fainting;
• from the respiratory system: bronchospasms, development of atelectasis;
• from the digestive system: nausea, constipation or diarrhea, vomiting, development of gastralgia, anorexia, cholestasis, spasms;
• from the urinary tract: decreased volume of daily diuresis, spasms of the ureters, impaired process of excretion of urine from the body;
• allergies: redness of the skin of the face, swelling of the face or trachea, general malaise, skin rashes, itching syndrome.

Exceeding the dosage of the drug can cause the following signs of overdose:

• increased cold sweating;
• clouding of consciousness;
• general malaise;
• increased nervous excitement;
• heart rhythm disturbance;
• anxiety syndrome;
• signs of psychosis;
• increased intracranial pressure;
• muscle weakness;
• convulsions;
• coma.

If such symptoms of overdose occur, carry out the necessary resuscitation measures.

Special instructions while taking the medicine

Special instructions that should be followed when prescribing and during the period of direct administration of the drug include:

1. If there is a risk of developing intestinal obstruction, the medication must be stopped.
2. If it is necessary to undergo surgery on the heart or something else with severe pain, stop taking Morphine the day before.
3. If nausea or vomiting occurs while taking the drug, concomitant use of a phenothiazine is permitted.
4. To reduce the side effects of the drug on the intestines, the use of laxatives is recommended.
5. Driving vehicles during treatment with Morphine must be done carefully, including activities that require increased attention.
6. It is recommended to discuss the combined use of antihistamines, hypnotics and psychotropic drugs, that is, those that affect the central nervous system, with your doctor.

No doctor can say exactly how long a person suffering from a malignant neoplasm of any location will live. Everything depends not so much on the individual characteristics of the body, but on the timeliness of prescribing appropriate treatment. For this reason, in order to avoid the use of such a strong drug as Morphine, it is recommended to consult a doctor at the first symptoms of the disease, when it occurs in the initial stage.

The word “morphine” (or the outdated name “morphine”) is known to almost everyone. But few people are familiar with the specifics of this substance and know about its properties. In the minds of most people, it is strongly associated with a drug. But is this really so?

Morphine's calling card

In medical terms, morphine is considered an alkaloid of opium. Its content was found in sleeping pill poppy, moonseed, and stephania.

Quite rarely found in varieties such as triclisia, croton, ocotea. Obtaining morphine is not difficult. The substance can be easily obtained from latex (dried juice) by first finely chopping unripe poppy pods. This alkaloid is found in opium in the form of sulfuric and lactic acids, as well as meconic salt. Its concentration can reach 26%, but on average this figure does not exceed 12%.

Origin of morphine

Morphine was first obtained at the very beginning of the 19th century. The progenitor of the substance is considered to be the German chemist Friedrich Serturner, who discovered this drug in 1804. But morphine's finest hour came much later - in 1857, when the first syringe was invented.

The German scientist considered it a good sleeping pill, and therefore named the substance in honor of the Greek god Morpheus. In addition, according to Serturner, this drug was a good substitute for opium, as a result of which it was successfully used to treat opium addiction. Positive results led to the fact that the dangerous consequences of using the substance were not immediately discovered.

No matter how paradoxical it may sound, its creator also became a victim of morphine. However, Serturner only realized towards the end of his life what was causing his illness. It turned out that morphine is even more addictive than opium. So in 1874 a new term arose - morphinism, meaning dependence on morphine. Moreover, psychological dependence arises very quickly, physical dependence a little slower.

Morphine - indications for use

However, in the case of morphine, not everything is so simple. If it is not abused, then it does not show its negative properties. This drug is still used in modern medicine. It appears as white crystals, which may become yellowish over time. The drug is available in tablets, ampoules and syringe tubes. Most often, the substance is used in the form of injections. Depending on the doctor’s prescription, it can be administered intravenously, intramuscularly, or subcutaneously.

Indications for use include:

• Severe physical pain, for example, during myocardial infarction, injuries, malignant tumors.
• With severe shortness of breath, cough, which are caused by heart failure.
• Before preparing for operations or in the postoperative period.
• For insomnia, especially if it is caused by severe pain.
• For X-ray examinations of the intestines to detect tumors or ulcers.

Morphine acts directly on the nervous system, thereby reducing pain. A physically healthy person, without lung or heart disease, can easily tolerate drug withdrawal. However, even in such cases, sometimes negative consequences appear: epileptic seizures, convulsions, suicide. Side effects of the substance can manifest themselves in the form of dizziness and increased intracranial pressure, bronchospasms and tachycardia, vomiting and nausea. Morphine should be prescribed especially carefully to children under 2 years of age. Since they are more sensitive, the effects of the drug sometimes cause unpredictable reactions

Signs of morphinism - addiction

As often happens, the medicinal drug has attracted the attention of drug addicts, because it improves mood, causes mild euphoria, and begins to act within 10 minutes. Moreover, this state can last up to 8 hours.

It is very easy to identify a morphine addict. It will always be given out:

• Watery eyes with a reddish tint and constricted pupils.
• Scars (and if hygiene is not observed, ulcers) on the skin at the injection site.
• Relaxation, apathy, lethargy and drowsiness.
• Incorrect bowel function - diarrhea or constipation.
• Temperature drop. Quite often there are cases when chills in combination with goose bumps give way to fever.

Consequences of morphine use

Uncontrolled use of the drug cannot lead to anything good. Such a person is more susceptible to various diseases of the lungs or heart, hepatitis, decreased immunity, and the development of encelopathy, which causes the death of brain cells. Withdrawal may begin 10-12 hours after the last dose of the drug. Withdrawal symptoms usually last up to 2 weeks.

Psychological dependence on morphine is terrible. Even if there is no physical need to use the substance, addicts still cannot cope with daily activities and think about the drug. This is why the percentage of relapses among such people is high (up to 96%). To get rid of psychological addiction, it is advisable to change the environment and determine the motivation for quitting drugs and healthy behavior.

Morphine is a well-known drug, an alkaloid of the opiate family. Do you remember Balabanov’s famous film, based on Bulgakov’s short story series “Notes of a Doctor”? It tells with documentary accuracy all the stages of the process of getting used to this drug and the sad outcome.

Paying attention to modern potent drugs, we have completely forgotten about morphine addicts. Yet they still exist today, and the opium alkaloid is considered a more accessible drug than spice or hashish. What is morphine, how can it be useful and how can it destroy a person - let’s talk about it.

Morphine is one of the oldest and most dangerous drugs

Morphine (also called “morphine”) was “given” to the world at the beginning of the 18th century by the young German pharmacist Friedrich Sertürner. A twenty-year-old boy was able to isolate a pure alkaloid, a white crystalline substance, from poppy opium. An inquisitive pharmacist not only obtained a new compound, he studied its effects on humans and experimental animals.

The founder of morphine was the German pharmacist Sertürner

Morphine got its name thanks to the Greek deity Morpheus, the god of dreams and astral adventures. After all, the main effect of the new drug was considered to be a powerful hypnotic effect.

Almost simultaneously, with a difference of only three years, morphine was discovered by Serturner’s colleague, the chemist from France Armand Seguin. The new drug gradually conquered the medical space. At first, it was used for medicinal purposes to a very limited extent.

Morphine is deadly to humans

But soon morphine became popular and became one of the most popular and widespread painkillers. But a surge in active interest in morphine began after one of the doctors proposed introducing the drug into the body by injection, under the skin. The triumphant march of the drug began in 1855.

Morphine: what is it?

Traditionally, this drug is obtained technologically by distilling the milky juice of an unripe poppy plant. A white powder with a crystalline structure, the opium alkaloid has poor dissolving ability. In medicine, a morphine solution is used, which is administered to a person by injection.

Medicinal abilities

In small and harmless doses, this remedy has numerous healing effects. The main effect of morphine is a sedative effect. It becomes especially necessary when, due to severe pain shock, the patient develops insomnia and the nervous system suffers.

Signs of morphine use in humans

About 100-120 years ago, morphine was prescribed for the treatment of delirium tremens, people suffering from mental illness and neuralgia.

Modern medicine has long been able to do without the use of opium alkaloid in the treatment of alcohol and other addictions. But our pharmaceutical industry has not yet abandoned the ancient remedy. In pharmacies you can find a lot of medicines created on the basis of this substance:

• Codeine;
• Skenan;
• Dionin;
• M-Eslon;
• Omnopon;
• Papaverine.

These medications act on brain receptors and stop the centers responsible for creating pain impulses. A person is saved from unbearable pain after an injury, a complex fracture, a heart attack, or the growth of a cancerous tumor.

Although such drugs contain a minimal dosage of morphine, even a small dose of the substance can do a person a disservice and turn him into a morphine addict. It has been proven that the addiction of people taking morphine is much stronger and stronger than that of the same opium addict.

The drug morphine

This drug is very dangerous, because small doses of it can provoke severe dependence in a person. Even at a low dosage that induces deep and restful sleep, the opium alkaloid changes emotional reactions, distorting the perception of reality.

Morphine addiction used to be widespread

What is the effect of morphine? When the alkaloid is administered in a minimal amount, the person experiences an elevated feeling of euphoria. His mood improves, the world is painted in rainbow and bright colors. A pleasant warmth is felt in the body. Wanting to experience a blissful feeling again, the person again turns for a new dose-injection and, unnoticed by himself, gradually increases the dosage.

Morphine has one peculiarity: if you stop taking it for a while (even a short one), the addict will have to start again with a small dose of the alkaloid. Otherwise, morphine will not give rosy emotions, but will bring serious discomfort and poisoning.

An overdose of morphine is very dangerous for humans. Excess of the drug causes severe intoxication of the body, accompanied by nausea and vomiting. When taken in large quantities, morphine is fatal.

Withdrawal syndrome

The drug morphine, after its withdrawal from the patient, produces a host of unpleasant side effects. The time when withdrawal begins manifests itself differently for each person. On average, this period is 10-20 hours. The following symptoms are characteristic of a morphine addict in withdrawal:

• confusion of speech;
• increased sweating;
• increased salivation;
• loss of consciousness and general weakness;
• slowing down of thought processes;
• hysteria and irritability, tearfulness.

How does morphine work in the next stage, with a more serious overdose? The following, more dangerous syndromes are added to the initial symptoms:

1. Loss of consciousness, onset of hallucinations, delirium.
2. The person completely refuses to eat food.
3. The individual has a strong tremor: trembling of the arms/legs.
4. The skin becomes covered with pimples, and a feeling of chills appears.
5. The pupils of the eyes dilate greatly, the drug addict is not able to visually assess the surrounding reality and understand where he is.

The effect of taking morphine occurs instantly

After another 1.5-2 days, the person visits the last, most severe stage of withdrawal syndrome. This period, if medicinal auxiliary measures are not taken, leads to the death of a person.. The following symptoms are observed:

• a sharp increase in blood pressure;
• severe tachycardia;
• aches of muscles and joints, cramps;
• cutting pain in the abdomen;
• nausea leading to profuse vomiting.

The emotional state of the morphine addict of this period is far from the feeling of euphoria that he experienced when he first became acquainted with the drug. Now morphine and morphine, there is no difference between them, have a depressing effect on a person.

A person, in search of a new dose, stops at nothing. She becomes aggressive, hysterical and unpredictable. In a fit of anger, an inadequate person is capable of harming others and even killing a person who is preventing the morphine addict from getting his next dose.

What does a morphine addict look like?

The portrait of a typical morphine addict is very far from the appearance of a healthy person. Now he is a thin, haggard and tired man. Sparse thin, greasy hair, wildly burning eyes. Puffy, swollen face with sallow skin, rotten, sore teeth. Due to frequent injections, a chronic morphine drug addict suffers greatly from the skin - it becomes covered with ulcers, ulcers and scars.

Ways to save a person from addiction

It is necessary to restore and return the individual to a healthy life in the conditions of a drug treatment clinic. What is morphine? It is an evil that gradually destroys a person, leading to his complete degradation and ultimate death. The detoxification process of morphine drugs takes a long time.

In case of observed attacks of rage and aggression, the patient is prescribed psychotropic drugs and tranquilizers. The overall picture of therapy is complemented by nutritional therapy with a specially designed diet and a course of multivitamin supplements. Psychotherapy is also often used.

In contact with

Systematic (IUPAC) name: (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

Trade names: MScontin, Oramorph, Sevredol, etc.

Use during pregnancy

Legality

Australia: controlled substance (S8)

Canada: List I

New Zealand: Class B

UK: Class A

USA: List II

UN: Schedules of Controlled Drugs I and III

℞ (available by prescription only)

Risk of developing addiction:

Physical: high

Psychological: medium-high

Risk of addiction: High

Application Inhalation (inhalation, smoking), inhalation (nasal), oral, rectal, subcutaneous, intramuscular, intravenous, epidural and intrathecal

Bioavailability 20–40% (oral), 36–71% (rectal), 100% (intravenous/intramuscular)

Protein binding 30–40%

Metabolism hepatic, 90%

Half life 2–3 hours

Excretion renal 90%, biliary 10%

Morphine (international nonproprietary name) is an opioid analgesic sold under hundreds of brand names. It is the main psychoactive substance contained in opium. The analgesic effect of morphine and other opioids (such as oxycodone, hydromorphone, and heroin) is based on their direct effect on the central nervous system. Morphine use is associated with rapid development of tolerance, tolerance, and psychological dependence, but physical dependence requires several months of continuous use to develop. Tolerance to effects such as respiratory depression and euphoria develops more quickly than to the analgesic effect. Many patients suffering from chronic pain can maintain treatment at the prescribed dose for years. However, the effects can quickly reverse, resulting in an increased pain threshold. Morphine is an opiate found abundantly in opium, the dried milk of the immature pods of the Papaver somniferum (opium poppy) plant. Morphine was the first active ingredient isolated from a plant source. It is one of (at least) 50 alkaloids from several groups present in opium, poppy straw concentrate, and other derivatives. The primary source of morphine is chemical extraction from opium. In the US, morphine is classified as Schedule II, in the UK it is Class A, and in Canada it is Schedule I. Morphine was first isolated in 1804 by Friedrich Sertürner. It is believed that morphine was the first alkaloid isolated from a plant in human history. In 1027, Merck began commercial sales of morphine. At that time, Merck was just one small pharmacy. Morphine became more widely used after the invention of the syringe in 1857. Serturner named the substance "morphium" after the Greek god of sleep, Morpheus, because the substance had the property of inducing sleep. Morphine is on the WHO Model List of Essential Medicines (a list of the most important medicines).

Use in medicine

Morphine is used mainly for the relief of severe short-term or prolonged pain, as well as pain associated with myocardial infarction and labor pain. However, there is an increased risk of mortality when using morphine in the setting of myocardial infarction without ST-segment elevation. Traditionally, morphine is also used to treat acute pulmonary edema. However, a 2006 report showed little evidence to support such practices. Immediate-release morphine is used to reduce symptoms of short-term shortness of breath (occurring as a result of cancer or other causes). For respiratory failure at rest or with minimal effort in cases of advanced cancer or late stages of cardiorespiratory disease, sustained-release morphine significantly reduces respiratory failure when used chronically in low doses, and its beneficial effects continue to be observed over the long term. The duration of the analgesic effect of morphine is about 3–4 hours (when administered intravenously, subcutaneously or intramuscularly) and 3–6 hours when administered orally. In Austria, Bulgaria and Slovenia, sustained-release morphine is also used in opiate substitution therapy (for drug users who cannot tolerate the side effects of methadone or buprenorphine or for those who are not suitable for these drugs).

Contraindications

Morphine should not be used for the following conditions:

Acute respiratory depression

Renal failure (due to accumulation of metabolites morphine-3-glucuronide and morphine-6-glucuronide)

Chemical poisoning (can be fatal for those with low tolerance)

Increased intracranial pressure, including with head trauma (risk of worsening respiratory depression)

Hepatic colic.

Although it was previously believed that morphine should not be used for acute pancreatitis, a review of the literature showed no evidence to support this statement.

Side effects

Constipation

Morphine, like other opioids such as loperamide, affects the myenteric plexus (a plexus of nerve cells that regulates intestinal motility) in the gastrointestinal tract, reducing intestinal motility and causing constipation. The gastrointestinal effects of morphine are mediated primarily by its action on mu-opioid receptors in the intestine. By inhibiting gastric emptying and reducing intestinal motility, morphine reduces intestinal transit. This is also facilitated by a decrease in intestinal secretion and increased intestinal absorption of fluids. Opioids may also indirectly affect the intestines by causing tonic spasms of the intestines as a result of inhibition of nitric oxide production. This effect was demonstrated in animal studies, where a nitric oxide precursor reversed the bowel motility-related side effects of morphine.

Hormonal imbalance

Clinical studies show that morphine, like other opioids, often provokes hypogonadism (a syndrome caused by decreased hormonal activity of the gonads; functional testicular failure, accompanied by a decrease in blood testosterone levels and characteristic clinical manifestations) and hormonal imbalance in regular users of both sexes. This side effect is dose dependent and occurs both in those who use morphine for therapeutic purposes and in drug users who use it recreationally. Morphine may affect menstruation in women because it suppresses luteinizing hormone levels. Multiple studies show that the majority (about 90%) of regular opioid users experience opioid-induced hypogonadism. This may increase the risk of osteoporosis and bone fractures in regular morphine users. Research shows that this effect is temporary. As of 2013, it is unclear what effects morphine has on the endocrine system at low doses or when taken for short periods of time.

Impact on test performance

Most evidence shows that opioids have minimal effects on tests assessing sensory, motor, and attention abilities. However, recent evidence has shown that morphine does have an effect on performance, which is not surprising given that it is a central nervous system depressant. Morphine disrupts the critical frequency of flickering (the critical frequency of flickering is the minimum frequency of flashes of light at which a feeling of continuous luminescence occurs), which is an indicator of general excitation of the central nervous system, and also worsens the performance of the Meddox test (a method for determining the nature and degree of heterophoria, in which in front of one eye of the subject place a Maddox stick and evaluate the deviation of the strip of light visible by this eye from the zero value on the Maddox scale), which is an indicator of the deviation of the optical axis of the eyes. Several studies have been conducted on the effects of morphine on motor performance; high doses of morphine can cause deterioration in the finger tapping test (the finger tapping test is a test of motor control. The patient is asked to press 4 buttons on the keyboard for a while (usually numbers) in a certain sequence, for example, 4-3-1-2 -4, after which the number of errors made is counted), as well as the ability to maintain a constant low level of isometric strength (i.e., fine motor skills are impaired), but there have been no studies of the effects of morphine on gross motor skills. Regarding the effects of morphine on cognition, one study found that morphine may promote anterograde and retrograde amnesia, however, these effects are minimal and temporary. In addition, short-term use of opioids in opioid-intolerant individuals has been associated with mild impairment of some sensory and motor abilities, and possibly also impairment in measures of attention and cognition. It is likely that such effects may only be observed in users who have not developed tolerance to morphine (so-called naïve users). In chronic morphine users (eg, those on chronic analgesic opioid therapy), behavioral testing results have generally demonstrated normal functioning in areas such as perception, cognition, coordination, and behavior. In one recent study of such patients, researchers tried to determine whether chronic morphine users could drive safely. Data from this study showed that chronic morphine users do not experience significant impairment in the abilities required to drive a motor vehicle (including physical, cognitive and perceptual aspects). The patients performed fairly quickly on tasks that required speed or reaction (for example, the Rey complex figure test, in which the subject is asked to redraw a complex figure and then draw it from memory), but the number of errors they made was higher than that of the control group. Patients on chronic analgesic opioid therapy do not demonstrate deficits in visuospatial perception and organization (as shown in the Wechsler test), but they do have deterioration in immediate and short-term visual memory (as shown in the Rey test, where you need to draw a complex figure from memory). ). These patients did not have impairments in higher order cognitive abilities (eg, planning ability). Patients had difficulty following instructions and exhibited impulsive behavior, although this did not reach statistical significance. Importantly, this study demonstrates that patients on opioid therapy do not exhibit deficits in any specific area, suggesting that opioid therapy has only minor effects on psychomotor, cognitive, or neuropsychological function. It is difficult to study the effects of morphine on performance without knowing why a person is using it. Opioid naïve subjects are volunteers who do not experience pain, unlike most regular morphine users. Pain is a stressor, so it can affect the performance of performance tests, especially tests that require a high degree of concentration. Pain can also vary, changing over time and differing among different people. It is unclear to what extent pain-related stress may precipitate impairment and what effect morphine has on these impairments.

addictive

Morphine has the potential to be a substance with a high risk of addiction. It is possible to develop both psychological and physical dependence, as well as tolerance. If a person is using morphine for severe pain, a combination of psychological and physical factors may be used to prevent the development of tolerance, but with long-term therapy, physical dependence and tolerance will inevitably develop. In controlled studies comparing the physiological and subjective effects of heroin and morphine in opiate-dependent individuals, patients did not show a preference for one of the drugs. Equally effective injectable doses of these drugs have similar mechanisms of action, without differences in subjective effects such as euphoria, ambition, nervousness, relaxation, lethargy and drowsiness. Short-term studies focusing on addiction have shown that tolerance to heroin and morphine develops at about the same rate. When compared with opioids such as hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former drug users showed a clear preference for heroin and morphine. Heroin and morphine are believed to be associated with a particularly high risk of abuse and addiction. These substances are also more associated with effects such as euphoria and other positive subjective effects compared to other opioids. The choice of these two drugs by former drug addicts may be due to the fact that heroin (also known as morphine diacetate, diamorphine or diacetyl morphine) is an ester of morphine and is the inactive form of morphine (which is converted to the active form in the body). Therefore, these substances are identical in vivo. Heroin is converted to morphine before binding to opioid receptors in the brain and spinal cord, after which the morphine exhibits its subjective effects that are so addictive to addicts. Other studies, such as an experiment called Rat Park. The essence of the experiment was that mice that had all the conditions for a full life, namely a large cage, an abundance of food and games, did not show a tendency to independently consume morphine, in contrast to mice that were kept under more restrictive conditions) indicate that morphine has a lower potential for developing physical dependence than is generally believed. Most studies of morphine addiction show that "highly stressed animals, like humans, will seek comfort in the drug." That is, mice placed in favorable conditions with plenty of living space, ample food and entertainment, company, exercise areas and personal space are less likely to become addicted to morphine. More recent studies have also shown that improved living conditions are associated with decreased morphine cravings in mice.

Tolerance

Tolerance to the analgesic effects of morphine develops quite quickly. There are several hypotheses regarding the mechanisms of development of tolerance, including: phosphorylation (incorporation of an orthophosphoric acid residue (H2PO3-) of the opioid receptor into the molecule (which will change the structure of the receptor); functional detachment of receptors from G-proteins (which leads to loss of receptor sensitivity); internalization of mu- opioid receptors (after ligand binding, many receptors are removed by endocytosis into the cell) and/or reduction in the number of receptors (reduction in the number of available receptors that morphine can act on) upregulation of the cAMP (cyclic adenosine monophosphate) pathway, which is a mechanism that antagonizes the effects of opioids. For a detailed discussion of these processes, see the article by Koch and Holt Cholecystokinin (a neuropeptide hormone produced by I cells in the duodenal mucosa and proximal jejunum) may mediate several antagonistic pathways by affecting opioid tolerance. Cholecystokinin antagonists (namely Proglumide) may slow the development of morphine tolerance.

Development of addiction and withdrawal syndrome

Discontinuation of morphine is associated with the development of classic opioid withdrawal syndrome, which, unlike withdrawal syndrome from barbiturates, benzodiazepines, alcohol or hypnotic drugs, is not fatal in itself (if we are talking about patients with a healthy nervous system, not having heart or lung problems). Withdrawal syndrome after withdrawal of morphine, as well as other opioids, occurs in several stages. Withdrawal symptoms following withdrawal from other opioids vary in intensity and duration. Weak opioids and mixed agonist-antagonists may cause short-term and mild withdrawal symptoms. So, the stages of withdrawal syndrome:

Stage I, 6-14 hours after last dose: desire to get high again, restlessness, irritability, sweating, dysphoria

Stage II, 14-18 hours after last dose: yawning, heavy sweating, slight depression, lacrimation, crying, moaning, rhinorrhea (excessive discharge of watery mucus from the nose), dysphoria, also intensification of the above symptoms, trance-like wakefulness

Stage III, 16-24 hours after dose: rhinorrhea, increase in the above symptoms, dilated pupils, piloerection (“goose bumps”), muscle cramps, hot flashes, paroxysmal feeling of cold, pain in bones and muscles, loss of appetite, onset of pain on the side gastrointestinal tract

Stage IV, 24-36 hours after dose: increase in all of the above symptoms, including severe cramps and involuntary leg movements, restless legs syndrome), loose stools, insomnia, increased blood pressure, slight increase in body temperature, increased respiratory rate and inspiratory volume, tachycardia (increased heart rate), anxiety, nausea

Stage V, 36-72 hours after dose: increase in the above symptoms, lying in the fetal position, vomiting, frequent loose stools, weight loss (2-5 kg ​​in 24 hours), increase in white blood cells and other changes in the blood

Stage VI, after the above symptoms: restoration of appetite and normal bowel function, the transition begins to initial and chronic symptoms, which are mainly psychological, but may also include increased sensitivity to pain, increased blood pressure, colitis or other gastrointestinal problems tract related to mobility, as well as problems with weight control

In the later stages of withdrawal, some patients have developed pancreatitis, which is thought to be due to spasm of the sphincter of Oddi. The withdrawal syndrome observed in drug addicts dependent on morphine usually lasts for the period of time between doses (6–12 hours). Early symptoms include watery eyes, insomnia, diarrhea, rhinorrhea, yawning, dysphoria, sweating, and in some cases, an uncontrollable urge to repeat the dose. As the syndrome develops, severe headaches, anxiety, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger cravings for the drug are observed. Severe depression and vomiting are common. During acute withdrawal symptoms, systolic and diastolic blood pressure and heart rate increase, which can potentially be associated with the risk of heart attack, blood clots, or stroke. Characteristic symptoms also include chills with the appearance of goose bumps, as well as fever, uncontrollable leg movements and heavy sweating. Severe pain in the bones and muscles of the back and limbs and muscle spasms may also occur. During withdrawal symptoms, it may be rational to take an appropriate drug to relieve symptoms. Withdrawal symptoms are most severe between 48 and 96 hours after the last dose, and gradually subside over 8-12 days. Abruptly stopping morphine by users who have become severely dependent can, in very rare cases, be fatal. Withdrawal syndrome after withdrawal of morphine is considered less dangerous than after withdrawal of alcohol, barbiturates or benzodiazepines. Psychological dependence on morphine develops complexly and gradually. Long after the physical need for morphine has ceased, the addict will continue to think and talk about his experiences with this and other substances and feel strange while sober. Psychological withdrawal following morphine withdrawal is usually a very long and painful process. It often causes victims to experience depression, anxiety, insomnia, mood swings, amnesia, confusion, paranoia and other symptoms. Without intervention, most significant physical symptoms, including psychological dependence, will disappear within 7-10 days. However, without changes in the physical environment or behavioral factors associated with the abuse, there is a high risk of relapse. An indicator of the potent additive nature of morphine is the relapse rate. Morphine (heroin) addicts have the highest relapse rates of all drug users (about 98%).

Overdose

Severe overdose, in the absence of immediate medical attention, can cause asphyxia and death due to respiratory depression. Treatment for overdose includes the use of naloxone. This drug completely blocks the effect of morphine, but provokes the immediate development of withdrawal symptoms in people with opiate addiction. Multiple doses may be required. The minimum lethal dose of morphine is 200 mg, but there have been cases of hypersensitivity in which 60 mg of the drug has been associated with sudden death. With strong dependence (and tolerance), a person can tolerate even a dose as high as 2000–3000 mg per day.

Pharmacodynamics

Endogenous opioids include endorphins, enkephalins, dynorphins, and morphine itself. Morphine mimics the effects of endorphins. Endorphins (full name - endogenous morphines) are responsible for effects such as analgesia (reduction of pain), sleep and feelings of pleasure. They are released in response to stimuli such as pain, strenuous exercise, orgasm, or arousal. Morphine is the prototype drug and is the standard substance to which all other opioids are compared. It interacts primarily with the μ–δ heteromer of the opioid receptor. μ-binding areas are scatteredly located in the human brain, with the greatest density in the posterior cerebellar amygdala, hypothalamus, thalamus, caudate nucleus, putamen and some cortical fields. They are also found on the terminal axons of primary afferents in laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the fifth cranial nerve. Morphine is a phenanthrene opioid receptor agonist. Its main action is to bind and activate the μ-opioid receptor in the central nervous system. In clinical studies, morphine exerts its main pharmacological actions in the central nervous system and gastrointestinal tract. Its main beneficial therapeutic effects are related to analgesia and sedation. Activation of the mu-opioid receptor is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a fast-acting drug that binds very strongly to mu-opioid receptors and for this reason it causes euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance and physical and psychological dependence when compared with other opioids in equivalent doses. Morphine is also an agonist at the κ-opioid and δ-opioid receptors. Effects on κ-opioid receptors are associated with spinal analgesia, pupillary constriction, and psychotomimetic effects. δ-opioid effects play a role in analgesia. Although morphine does not bind to the σ receptor, σ agonists such as (+)-pentazocine have been shown to inhibit morphine-induced analgesia and that σ antagonists enhance analgesia, suggesting involvement of the σ opioid receptor in the actions of morphine. The effects of morphine may be inhibited by opioid antagonists such as naloxone and naltrexone; the development of morphine tolerance can be suppressed by NMDA antagonists such as ketamine or dextromethorphan. Alternate use of morphine and chemically different opioids over a long period of time can reduce the development of tolerance over the long term. This is especially true for substances that have incomplete cross-tolerance with morphine, such as levorphanol, ketobemidone, pyritramide and methadone and their derivatives; all of these substances are also NMDA antagonists. The most potent opioids with the least cross-tolerance with morphine are thought to be methadone or dextromoramide.

Gene expression

Research has shown that morphine can change the expression of a number of genes. A single injection of morphine alters the expression of two major groups of genes, proteins involved in mitochondrial respiration and proteins related to the cytoskeleton.

Impact on the immune system

It has long been known that morphine acts on receptors expressed on cells in the central nervous system, resulting in decreased pain and analgesia. In the 1970s and 80s, evidence emerged that those with opioid addiction had an increased risk of developing infections (such as pneumonia, tuberculosis and HIV/AIDS), leading to the development of the theory that morphine affects the immune system . This has led to an increase in research into the effects of long-term morphine exposure on the immune system. The first step in this direction was the discovery that opioid receptors expressed on cells of the central nervous system are also expressed on cells of the immune system. One study found that dendritic cells, which are part of the innate immune system, have opioid receptors. Dendritic cells are responsible for the production of cytokines, which in turn are responsible for communicating with the immune system. The same study found that dendritic cells that were treated long-term with morphine as they differentiated produced more interleukin-12 (IL-12), a cytokine responsible for the proliferation, growth and differentiation of T cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), the cytokine responsible for mounting the B cell immune response (B cells produce antibodies to fight infections). This cytokine regulation occurs through the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Normally, p38 within dendritic cells expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes phosphorylation of p38 MAPK. This phosphorylation activates p38 MAPK, promoting the production of IL-10 and IL-12. With prolonged exposure of dendritic cells to morphine during their differentiation and subsequent treatment with LPS, cytokine production is altered. Following morphine exposure, p38 MAPK does not produce IL-10, favoring IL-12 instead. The exact mechanism by which one cytokine is favored is unknown. It is more likely that morphine increases phosphorylation of p38 MAPK. Interactions at the transcriptional level between IL-10 and IL-12 may cause a further increase in IL-12 production while IL-10 is not produced. Increased production of IL-12 causes an increase in T cell immune response. Further research into the effects of morphine on the immune system showed that morphine induces the production of neutrophils and cytokines. Because cytokines are produced in part as an immediate immunological response (inflammation), it has been suggested that they may also cause pain. Thus, cytokines may be a logical target of analgesic development. A recent study assessed the effects of morphine on short-term immunological responses in animals. Parameters such as pain threshold and cytokine production after hind paw transection were measured. Typically, with wounding, cytokine production in and around the wounded area increases to suppress infection and control healing (and possibly pain), but administration of morphine prior to hind paw transection at 0.1-10.0 mg/kg caused a decrease in cytokines around the wound in a dose-dependent manner. . The authors suggested that morphine use in the post-injury period may reduce resistance to infection and may negatively impact wound healing.

Pharmacokinetics

Absorption and Metabolism

Morphine can be used orally, sublingually (under the tongue), buccally (behind the cheek), rectally, subcutaneously, intravenously, nasally, intrathecally (into the subarachnoid space of the spinal cord), or epidurally (into the epidural space of the spine through a catheter), or inhaled through an inhaler. On the streets, the drug is most often inhaled lately, but in medical institutions morphine is administered intravenously. Morphine undergoes extensive first-pass metabolism (the majority is broken down in the liver), so when taken orally, only 40–50% of the dose reaches the central nervous system. Plasma levels observed after subcutaneous, intramuscular and intravenous administration are approximately equal. Following intramuscular or subcutaneous administration, plasma morphine levels reach peak levels within approximately 20 minutes and after oral administration within half an hour. Morphine is metabolized primarily in the liver and approximately 87% of the morphine dose is excreted in the urine within 72 hours of administration. Morphine is metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by the second-phase metabolic enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6–10% is converted to M6G. Metabolism does not only take place in the liver, but can also be observed in the brain and kidneys. M3G does not bind to the opioid receptor and has no analgesic effect. M6G binds to mu receptors and is half as potent an analgesic as morphine (in humans). Morphine can also be metabolized into small amounts of normorphine, codeine and hydromorphone. Metabolic rate depends on age, diet, genetic makeup, presence of diseases and use of other medications. The half-life of morphine is approximately 120 minutes, although there may be slight differences between men and women. Morphine can be stored in fatty tissue, thus being detectable in the body after death. Morphine can cross the blood-brain barrier, but due to its low lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not easily cross this barrier. Diacetylmorphine, a morphine derivative, is able to cross the blood-brain barrier more easily, making it a more potent drug. There are also sustained-release oral morphine formulas that last significantly longer than morphine, allowing for use as little as once a day.

Detection in biological fluids

Morphine and its major metabolites, morphine-2-glucuronide and morphine-6-glucuronide, can be detected in blood, plasma, hair and urine by immunoassay. Chromatography can be used to test each substance separately. In some testing procedures, metabolic products are hydrolyzed into morphine prior to immunoassay, which is worth considering when comparing morphine levels in separately published results. Morphine can be isolated from whole blood using solid phase extraction and detected using liquid chromatography-mass spectrometry techniques. Consuming codeine or food containing poppy seeds may give false positive results. A 1999 analysis found that relatively small doses of heroin (which are immediately metabolized into morphine) show up in standard urine tests within 1 to 1.5 days of use. A 2009 analysis found that when the analyte is morphine and the detection limit is 1 ng/mL, an intravenous dose of morphine equal to 20 mg is detectable within 12–24 hours. The detection limit of 0.6 ng/ml has similar performance.

Natural sources

Morphine is the most abundant opiate found in opium, the dried milky juice extracted when the immature pods of the opium poppy (Papaver somniferum) are cut slightly. Morphine was the first active narcotic compound discovered in plants and is one of at least 50 alkaloids of various types present in opium, poppy straw concentrate, and other poppy derivatives. Morphine makes up 8-14% of the dry weight of opium, although some specially grown varieties contain up to 26% morphine or, conversely, minimal amounts (less than 1%, or about 0.04%). Low morphine grades ("Przemko" and "Norman") are used to produce other alkaloids such as thebaine and oripavine, which in turn are used in the production of semi-synthetic and synthetic opioids such as oxycodone and etorphine and other substances. P. bracteatum does not contain morphine or codeine or other narcotic alkaloids of the phenanthrene type. This species is a good source of thebaine. Morphine content has not been confirmed in other species (Ranunculaceae and Poppy), as well as in some types of hops and mulberries. Morphine is produced primarily early in the plant's life cycle. Various processes occurring in the plant contribute to the production of codeine, thebaine and in some cases small amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine and hydrocodone (these compounds are often synthesized from thebaine and oripavine). The human body produces endorphins, which are endogenous opioid peptides that act as neurotransmitters and exhibit morphine-like effects.

Chemistry

Morphine is a benzylisoquinoline alkaloid with two additional ring closures. He has:

Most illicit morphine is used to produce codeine through methylation. It is also a precursor for the production of many drugs, including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone); many morphine derivatives can be produced using thebaine and/or codeine as starting material. Replacing the N-methyl group of morphine with an N-phenylethyl group results in the production of a substance 18 times more potent than morphine (relative to opiate agonism). Combining this modification with the replacement of the 6-hydroxyl group with a 6-methylene group creates a compound that is 1.443 times more potent than morphine and, by some measures, more potent than opioids synthesized by Bentley such as etorphine (M99, Immobilon® tranquilizer). The structure-activity relationships of morphine have been well studied. As a result of research and use of this molecule, more than 250 morphine derivatives (including codeine) have been discovered since the late 19th century. These drugs demonstrate from approximately 25% of the analgesic potential of codeine (or slightly more than 2% of the potential of morphine), to levels several thousand times greater than the potential of morphine. The most powerful opioid antagonists are naloxone (Narcan®), naltrexone (Trexan®), diprenorphine (M5050, a drug that reverses the effects of the drug Immobilon®) and nalorphine (Nalline®). Some opioid agonist-antagonists, partial agonists, and inverse agonists have also been produced from morphine. The receptor activation profile of these semisynthetic morphine derivatives varies significantly. Some of the derivatives, such as apomorphine, exhibit no narcotic effects at all. Morphine and most of its derivatives do not exhibit optical isomerism, unlike some more distantly related derivatives, such as the morphinan substances (levorphanol, dextorphan, and the racemic parent compound dromorane). Agonist-antagonist substances have also been synthesized from morphine. Elements of the structure of morphine have been used to create completely synthetic drugs, such as drugs of the morphinan family (levorphanol, dextromethorphan, and others). Other groups of drugs include many substances with morphine-like properties. Modification of morphine and the synthetic substances mentioned above made it possible to synthesize non-narcotic drugs with a different mechanism of action, such as emetics, stimulants, antitussives, cough suppressants, muscle relaxants, local anesthetics, general anesthetics and other drugs. Most semisynthetic opioids, both morphine and codeine, are created by modifying one or more of the following elements:

Halogenation or other modifications at positions 1 and/or 2 on the morphine carbon skeleton.

Removal or return of the methyl group that converts morphine to codeine, or replacement of the methyl group with another functional group (ethyl or other) to produce codeine analogues from morphine-derived drugs and vice versa. Morphine-based codeine analogs are often used as a prodrug of a stronger drug, such as codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc.

Saturation, opening or other changes in the connection between positions 7 and 8, as well as the addition, deletion or modification of functional groups at these positions; saturation, reduction, removal or other modification of the 7-8 bond and addition of a functional group on the hydromorphinol; oxidation of the hydroxyl group to a carbonyl group and the change of the 7-8 double bond to a single bond converts codeine to oxycodone.

Addition, removal or modification of functional groups at positions 3 and/or 6 (dihydrocodeine and related substances, as well as hydrocodone and nicomorphine); by moving the methyl functionality from position 3 to position 6, codeine becomes heterocodeine, which is 72 times more potent, and thus 6 times more potent than morphine

Addition of functional groups or other modifications at position 14 (oxymorphone, oxycodone, naloxone)

Modifications at positions 2, 4, 5 or 17, usually along with other changes in the morphine molecule. This is usually done with drugs produced by catalytic reduction, hydrogenation, oxidation and similar reactions to produce potent morphine and codeine derivatives

Both morphine and its hydrate form, C17H19NO3H2O, are sparingly soluble in water. Only 1 gram of hydrate dissolves in five liters of water. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts from this drug, which are 300 times more soluble in water than the parent molecule. The pH of saturated morphine is 8.5, while the salts are acidic. Because they are derivatives of a strong acid but a weak base, they both have a pH of 5; and, as a consequence, for injection use, morphine salts are mixed with a small amount of NaOH. A large number of morphine salts are used, the most commonly used in clinical settings are the hydrochloride, sulfate, tartrate, and citrate; less commonly used are methobromide, hydrobromide, hydroiodide, lactate, chloride and bitartrate and other substances listed below. Morphine diacetate, otherwise known as heroin, is a Schedule I controlled substance in the United States, and for this reason is not used in medicine. In the UK, Canada and some European countries, this substance is sanctioned. In the UK, heroin has a fairly wide use (comparable to the use of hydrochloride salt). Morphine meconate is the main form of the alkaloid contained in poppy, in addition to which it contains substances such as morphine pectinate, nitrate, sulfate and others. Like codeine, dihydrocodeine and other opiates, especially older ones, some manufacturers use morphine as a salicylic acid ester that is easily mixed with other substances, allowing for the therapeutic benefits of opioids and NSAIDs; in the past, various barbyurate salts of morphine were also used, for example morphine valerate (a salt of this acid is the active substance of valerian). Calcium morphenate is an intermediate substance in the production of morphine; sodium morphenate is less commonly used. Morphine ascorbate and other salts such as tannate, citrate and acetate, phosphate, valerate and others may be present in maca, depending on the preparation method. Industrially produced morphine valerate was used as an ingredient in Trivaline, a drug available for oral and parenteral use popular many years ago in Europe and other countries (not to be confused with the herbal remedy of the same name), which also included caffeine and cocaine, with a version containing codeine valerate as the fourth ingredient being sold under the cake name Tetravalin. Closely related to morphine are the opioids morphine-N-oxide (genomorphine), a pharmaceutical substance that is not currently used, and pseudomorphine, an opium alkaloid that forms as a breakdown product of morphine.

Morphine synthesis

Biosynthesis

Morphine is biosynthesized from tetrahydroisoquinoline reticuline. It is converted to salutaridine, thebaine and opivarine. Enzymes involved in this process include salutaridin synthase, salutaridin:NADP 7-oxidoreductase and codeinone reductase.

Chemically synthesis

First total synthesis of morphine, developed by Marshall D. Gates Jr. in 1952, widely used today. Several other synthesis methods have been developed by the research groups of Rice, Evans, Fook, Parker, Overman, Mülser-Trauner, White, Taber, Trost, Fukiyama, Gillow, and Stork.

Production

Opium poppy alkaloids are associated with meconic acid. The production method is extraction from crushed plants using dilute sulfuric acid, a stronger acid than meconic acid but not so strong as to react with the alkaloid molecules. Extraction is performed in several stages (one part of the crushed plant is extracted 6-10 times, so almost all alkaloids are present in the solution). From the solution obtained at the last stage of extraction, alkaloids are precipitated using ammonium hydroxide or sodium carbonate. The final step is the purification and separation of morphine from other opium alkaloids. In Britain during World War II, a similar synthesis method was developed called the Gregory process, which begins by stewing the whole plant, in most cases with roots and leaves intact, in slightly acidified water, followed by steps of concentration, extraction, and purification of the alkaloids. Other methods of processing poppy straw (i.e. raw pods and stems) involve evaporation using one or more types of alcohols or other organic solvents. Poppy straw is used mainly in continental Europe and the British Commonwealth, and poppy juice is most often used in India. When using milky juice methods, vertical or horizontal cuts are made on the unripe pods with a knife with 2-5 blades with a stop specially designed for this purpose, allowing cutting to a depth of up to 1 mm. Incisions can be made up to 5 times. In the past, alternative methods using milky sap were used in China. These methods involved cutting off the poppy heads, threading large needles through them, and collecting the dried sap after 24 to 48 hours. In India, opium is grown on farms by licensed farmers. In special government centers it is dried to a certain level and then sold to pharmaceutical companies that extract morphine from opium. In Turkey and Tasmania, morphine is obtained by growing and processing whole, dried, mature pods with stems called "opium straws." Turkey uses a water extraction process, while Tasmania uses a solvent extraction process. The opium poppy contains at least 50 different alkaloids, but most of them are present in very low concentrations. Morphine is the main alkaloid found in raw opium and makes up ~8-19% of opium's dry weight (depending on growing conditions). Some specially grown poppies contain up to 26% opium by weight. A very rough estimate of the morphine content of crushed poppy straw can be obtained by dividing the percentage expected from the milky sap method by 8 or by an empirically determined factor which is a number between 5 and 15. The Norman cultivar P. somniferum, also developed in Tasmania , produces less than 0.04% morphine, but higher amounts of thebaine and oripavine, which can also be used to synthesize semisynthetic opioids and other drugs such as stimulants, emetics, opioid antagonists, anticholinergics and smooth muscle agents. In the 1950s and 1960s, Hungary supplied almost 60% of all morphine used in medicine. Today, poppy cultivation is legal in Hungary, but the size of poppy fields is limited by law to two acres (8,100 m2). It is legal to sell dried poppies in flower shops for decorative purposes. In 1973, it was announced that a team from the National Institutes of Health in the United States had developed a method for the total synthesis of morphine, codeine and thebaine using coal tar as a starting material. The initial objective of the research was the invention of codeine-hydrocodone class cough suppressants (which can be produced in several steps from morphine as well as codeine or thebaine). Most of the morphine produced for pharmaceutical use worldwide can be converted to codeine, since the concentration of the latter in raw opium and poppy straw is much lower than that of morphine; In most countries of the world, the use of codeine (both as a final product and as a precursor) is as widespread as the use of morphine.

Precursor for the production of other opioids

Pharmaceuticals

Morphine is a precursor in the production of a large number of opioids, such as dihydromorphine, hydromorphone, hydrocodone and oxycodone, as well as codeine, which itself has a large number of semisynthetic derivatives. Morphine is often treated with acetyl anhydride and set on fire to produce heroin. Doctors in Europe are increasingly recognizing the need to use slow-release oral morphine as substitution therapy instead of methadone and buprenorphine for patients unable to tolerate the side effects of the latter. Slow-release oral morphine has been widely used as opiate maintenance therapy for many years in Austria, Bulgaria and Slovakia. In other countries, including the UK, it is also used, but on a smaller scale. Extended-release morphine has a long-lasting effect, mimicking the effects of buprenorphine, maintaining constant blood levels, without peaks or a noticeable “high”, but also without the development of withdrawal symptoms. In addition, slow-release orally administered morphine is a promising treatment for opiate-dependent patients who are sensitive to the side effects of buprenorphine and methadone due to their unnatural pharmacological actions. Heroin and morphine have almost identical pharmacology, except that the heroin molecule has two acetyl groups, which increases its fat solubility, allowing the latter to cross the blood-brain barrier faster and reach the brain when injected. Upon reaching the brain, these acetyl groups are removed and the substance is converted into morphine. Thus, heroin can be considered a faster-acting form of morphine.

Illegal production and use

Morphine is produced illegally in several ways. Rarely, this process uses codeine, which is found in cough suppressants and prescription pain relievers. This dimethylation reaction often occurs using pyridine and hydrochloric acid. Another source of illicitly produced morphine is sustained release morphine, such as the MS-Contin formula. Morphine can be isolated from these products by simple extraction, resulting in a morphine solution suitable for injection use. As an alternative to this route of administration, morphine tablets can be crushed into a powder and inhaled through the nose, mixed with water and injected, or simply swallowed. However, with this use, the user will not experience the full extent of euphoria, but the effect will last longer. Due to its sustained release, the MS-Contin formula is used in some countries along with methadone, dihydrocodeine, buprenorphine, dihydroethorphine, pyritramide, levo-alpha acetylmethadol (LAAM) and special 24-hour hydromorphone formulas as maintenance therapy and for detoxification of patients who are physically dependent on opioids. In addition, morphine can be converted into heroin or another stronger opioid through various chemical reactions. Using special technology (where the original precursor is codeine), morphine can be converted into a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine and codeine derivatives such as acetylcodeine. Since heroin is one of a series of 3,6 dibasic esters of morphine, morphine can be converted to nicomorphine (Whelan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicyloylmorphone with the corresponding acid anhydrides. Crystalline acetic acid can be used to obtain a substance containing large amounts of 6-monoacetylmorphine, niacin (vitamin B3).

Story

The creation of an elixir based on opium is attributed to alchemists of Byzantine times, but during the Ottoman conquest of Constantinople (Istanbul) the exact formula was lost. Around 1522, Paracelsus wrote about an opium-based elixir, which he called laudanum (from the Latin laudare, meaning “praise”). He described it as a potential pain reliever but recommended using it in moderation. In the late 18th century, when the East India Company began trading opium throughout India, another opiate called laudanum gained popularity among doctors and their patients. Friedrich Serturner first discovered morphine as the first active alkaloid isolated from opium in December 1804 in Paderborn, Germany. In 1817, Serturner and Company brought the drug to market as an analgesic and as a treatment for alcohol and opium addiction. In 1827, commercial sales of morphine began in a pharmacy in the German city of Darmstadt. This pharmacy would later become the pharmaceutical giant Merck, largely thanks to its sales of morphine. Morphine was later discovered to be much more addictive than alcohol or opium. The extensive use of morphine during the American Civil War resulted in more than 400,000 cases of so-called “soldier's disease,” or morphine addiction. This idea became the subject of controversy, as there was speculation that the very existence of such a disease was fabricated; The first documented mention of the phrase “soldiers’ diseases” occurs in 1915. Diacetylmorphine (also known as heroin) was synthesized from morphine in 1874. In 1898 it was brought to market by Bayer. Heroin is approximately 1.5-2 times stronger than morphine on a weight basis. Due to the fat-soluble nature of heroin, it can cross the blood-brain barrier faster than morphine, greatly increasing its potential for addiction. One study using a variety of subjective and objective methods showed that the relative potency of heroin relative to morphine (when administered intravenously to former drug users) was 1.80–2.66 mg of morphine sulfate per 1 mg of diamorphine hydrochloride (heroin). In 1914, the US passed the Harrison Drug Tax Act, making morphine a controlled substance and making it a criminal offense to possess without a prescription. Until heroin was first synthesized, morphine was the most popular narcotic analgesic in the world. In general, until the synthesis of dihydromorphine (circa 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there were no drugs in the world that could compare in effectiveness to opium , morphine and heroin (the first synthetic opioids, such as pethidine, synthesized in Germany in 1937, would not be invented until a few years later). Codeine analogues and derivatives such as dihydrocodeine (Paracodine), ethylmorphine (Dionine), and benzylmorphine (Peronine) were semisynthetic opioid agonists. Even today, heroin addicts prefer morphine to all other opioids (unless they can get heroin). Under certain conditions (lack of available morphine), hydromorphone, oxymorphone, high-dose oxycodone or methadone (as in the 1970s in Australia) are the preferred options. The most commonly used "stop-gap" measures used by heroin addicts to ease withdrawal are codeine, as well as dihydrocodeine and poppy straw derivatives such as poppy pod and poppy seed tea, propoxyphene and tramadol. The structural formula of morphine was determined in 1925 by Robert Robinson. At least 3 methods have been patented for the total synthesis of morphine from materials such as coal tar and petroleum distillates, with the first method being described in 1952 by Dr. Marshall D. Gates Jr. at the University of Rochester. Despite this, most morphine is still obtained from the opium poppy, either through traditional methods (harvesting the milky sap from the unripe poppy fruit) or through processes using poppy straws, dried pods and plant stems (the most popular method was invented in 1925 and described in 1930 by the Hungarian chemist Janos Kabai). In 2003, endogenous morphine produced in the human body was discovered. It took scientists 30 years of debate and guesswork to achieve this. It was known that the human body has a receptor that responds only to morphine, the μ3-opioid receptor. Trace amounts of endogenous morphine have been found in human cells that form in response to neuroblastoma cancer cells.

Society and culture

Legal status

Illegal use

Euphoria, complete suppression of stress and all aspects of pain (“suffering”), increased empathy and talkativeness, pleasant sensations in the body and relief of anxiety symptoms (anxiolysis) are the effects that most often cause psychological dependence and, therefore, are the main cause of opiate overdose , and in the absence of a dose - severe withdrawal syndrome. As the prototype of an entire class of drugs, morphine shares all of their characteristics and has a high potential for abuse. Society's attitude towards drugs is largely determined by its attitude towards morphine addiction. Animal and human studies and clinical data support the contention that morphine is one of the most euphoric substances on the planet, and that morphine and heroin cannot be distinguished by any route of administration (except intravenous) because heroin is a prodrug for the delivery of morphine to the body. . Chemical modification of the structure of the morphine molecule allows the production of other euphoric substances such as dihydromorphine, hydromorphone (Dilaudid, Hydal) and oxymorphone (Numorphan, Opana), as well as the three methylated equivalents of the latter (dihydrocodeine, hydrocodone, oxycodone). Apart from heroin, the 3,6 morphine esters category includes dipropanoylmorphine, diacetyldihydromorphine and other substances such as nicomorphine and other semi-synthetic opioids such as desomorphine, hydromorphinol, etc. In general terms, morphine abuse includes taking more than prescribed by a doctor or using morphine without a prescription or medical supervision, making and using injections of morphine tablets, mixing morphine with substances such as alcohol, cocaine and the like to enhance its effects , and/or using methods that interfere with the mechanism of action of extended-release morphine, such as chewing or crushing tablets and then inhaling them or making injections. The latter method is very time-consuming and is used along with traditional methods of smoking opium. Morphine is rarely found as a street drug, although it is used where it is available in the form of injection ampoules, pure pharmaceutical powder and dissolvable tablets. Morphine is also available as a paste, which is used in the production of heroin, which can be smoked or converted into a soluble salt and injected. Poppy straw, like opium, can contain morphine, the purity of which ranges from the purity of poppy tea to almost pharmaceutical levels (and the final substance may contain not only morphine, but also the other 50 alkaloids present in opium).

Slang terms

On the streets, morphine is called “M”, “sister morphine”, “vitamin M”, “morpho”, etc. MS Contin tablets are called "misties" and the 100 mg sustained release tablets are called "gray" or "blockbuster" tablets. A speedball is a mixture of substances in which some elements cancel out others, for example, morphine may be mixed with cocaine, amphetamines, methylphenidate or similar drugs. The injectable combination drug Blue Velvet is a mixture of morphine with the antihistamine Tripelennamide (Pyrabenzamine, PBZ, Pelamine), and is less commonly used as an enema; the same term refers to a mixture of tripelennamine and dihydrocodeine or codeine tablets or syrups taken orally. "Morphia" is the obsolete official name for morphine and is also used as a slang term. Driving Miss Emma is morphine taken orally. All-purpose tablets (instant dissolving hypodermic tablets that can also be administered orally or sublingually or buccally) and some brand names for hydromorphone are also called "Shake & Bake" or "Shake & Shoot". Morphine (especially diacetylmorphine, i.e. heroin) can be smoked, also called "Chasing The Dragon". The process of relatively crude acetylation to convert morphine into heroin and related substances immediately before use is called "AAing" (Acetic Anhydride) or "home-bake", and the final product is also called "home-bake" or "blue". heroin" (not to be confused with "Blue Magic" (100% pure heroin), or with cough syrup called Blue Morphine or Blue Morphone, or "Blue Velvet").

Availability of morphine in developing countries

Despite the cheapness of morphine, people in poor countries often cannot afford to buy it. According to 2005 data provided by the International Narcotics Control Board (established in 1964 under the 1961 Convention, consisting of 13 members elected by ECOSOC for 5-year terms and serving in their personal capacity), 79% of morphine is consumed in 6 countries of the world - Australia, Canada, France, Germany, the United Kingdom and the USA. Less wealthy countries, where 80% of the world's population lives, consume only about 6% of morphine. Some countries have effectively banned the import of morphine, while in others the substance is virtually unavailable even to relieve severe pain if a person is dying. Experts believe morphine's unavailability is due to its potential for addiction. However, despite these characteristics of morphine, many Western doctors believe in the consistency of its use with a subsequent gradual reduction in dose at the end of treatment.

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List of used literature:

"Morphine sulfate". The American Society of Health-System Pharmacists. Retrieved $1 $2. Check date values ​​in: |accessdate= (help)